Malonic acid derivatives

ABSTRACT

This invention relates to a malonic acid derivative represented by the general formula (I) ##STR1## wherein R 1  and R 2 , which may be the same or different, represents hydrogen atom; C 1  -C 12  alkyl group; C 1  -C 8  alkyl group substituted with C 1  -C 5  alkoxy group, a tetrahydrofuryl group, a phenyl group or a phenyl group substituted with 1 to 3 groups selected from the group consisting of halogen atoms, C 1  -C 5  alkyl groups and C 1  -C 5  alkoxy groups; or C 2  -C 6  alkenyl group; R 3  and R 4 , which may be the same or different, represent hydrogen atom, C 1  -C 6  alkyl group, C 2  -C 6  alkenyl group, C 2  -C 8  alkoxyalkyl group, benzoyl group, C 2  -C 8  alkylcarbonyl group, C 2  -C 8  alkoxycarbonyl group, C 1  -C 4  alkylsulfonyl group or aralkyl group including benzyl group, and R 5 , R 6  and R 7 , which may be the same or different, represent hydrogen atom or C 1  -C 4  alkyl group, and its pharmaceutically acceptable salts, a process for producing the same and a pharmaceutical composition containing the same.

FIELD OF THE INVENTION

This invention relates to a malonic acid derivative represented by thegeneral formula (I) ##STR2## wherein R¹ and R², which may be the same ordifferent, represent hydrogen atom; C₁ -C₁₂ alkyl group; C₁ -C₈ alkylgroup substituted with C₁ to C₅ alkoxy group, a tetrahydrofuryl group, aphenyl group or a phenyl group substituted with 1 to 3 groups selectedfrom the group consisting of halogen atoms, C₁ -C₅ alkyl groups and C₁-C₅ alkoxy groups; or C₂ -C₆ alkenyl group; R³ and R⁴, which may be thesame or different, represent hydrogen atom, C₁ -C₆ alkyl group, C₂ -C₆alkenyl group, C₂ -C₈ alkoxyalkyl group, benzoyl group, C₂ -C₈alkylcarbonyl group, C₂ -C₈ alkoxycarbonyl group, C₁ -C₄ alkylsulfonylgroup or aralkyl group (e.g., benzyl group), and R⁵, R⁶ and R⁷, whichmay be the same or different, represent hydrogen atom or C₁ -C.sub. 4alkyl group, and its pharmaceutically acceptable salts, a process forproducing the same and a pharmaceutical composition containing the same.

BACKGROUND OF THE INVENTION

There are known various malonic acid derivatives capable of curing liverdisorders in men and animals in the art. Among them is illustratedMalotilate (disclosed in U.S. Pat. No. 4,118,506) as a typical one.There is still a desire, however, for a compound capable of curingand/or preventing liver disorders at a considerably lower dosage whichwill provide a more safety margin for treating both men and animals.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a malonicd acidderivatives represented by the aforementioned general formula (I).

The other object of the present invention is to provide a pharmaceuticalcomposition containing as an active ingredient a compound shown by saidgeneral formula (I).

The further other object of the present invention is to a provide amethod for treating liver disorders in men and animals by administratingsaid composition to them parenterally or orally.

The further other object of the present invention is to provide a methodfor producing a compound represented by said general formula (I).

The terms "alkyl and alkenyl" as used herein denote both straight-chainand branched alkyl and alkenyl groups, respectively.

The compounds represented by the aforementioned general formula (I) andtheir salts are novel compounds not described in the literatures; theyhave, for example, a liver function activating effect, and hence isuseful as active ingredient fora pharmaceutical composition for treatinghepatic disorders in men and animals.

The compound of general formula (I) can be produced, for example, bymethods A, B and C as shown in the following scheme:

Method A ##STR3## wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the samemeanings as defined above, M represents alkali metal atom.

That is, the compound of the general formula (I) can be produced byreating the compound of the general formula (II) with the compound ofthe general formula (III) in a suitable solvent at a temperature in therange of from -20° C. to 80° C. and followed by the reaction with thecompound of the general formula (IV) at a temperature in the range offrom -20° C. to 80° C.

The compound of general formula (II) shown below can be obtained byreacting a compound of general formula (V) with an equimolar or aslightly excess of sodium bisulfite in water at a temperature in therange of from 0° C. to 80° C. ##STR4## Then, the compund of the generalformula (IV) can be synthesized by the known method as shown in thefollowing scheme: ##STR5##

Method B ##STR6## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and M have the samemeanings as defined above.

That is, the compound of the general formula (I) can be produced byreacting the compound of the general formula (V) with the compound ofthe general formula (III) in a suitable solvent at a temperature in therange of from -20° C. to 80° C. and followed by the reaction with thecompound of the general formula (IV) at a temperature in the range offrom -20° C. to 80° C. The reaction mentioned above can be acceleratedby the addition of sodium bisulfite.

The solvents which can be used in Method A or B are preferably water orsolvents consist of water and an organic solvent. For the organicsolvent, there can be exemplified alcohol (e.g., methanol, ethanol),acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide,hexamethylphosphoroamide and N,N-dimethylethyleneurea or in combinationof these solvents.

Method C ##STR7## wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the samemeanings as difined above, R^(4') represents hydrogen atom or C₁ -C₅alkyl group, and X represents a halogen atom.

That is, the compound of the general formula (I) can be produced byreacting the compound of the general formula (I'), which was prepared bythe method A or B, with the compound of the general formula (VI) or(VII) in an inert solvent at a temperature in the range of from -20° C.to the boiling point of the solvent used.

Solvents which can be used in this reaction may be any of those notdisturbing the reaction, and include for example ethers (e.g. diethylether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene,toluene, xylene), halogenated hydrocarbons (e.g. chloroform, carbontetrachloride). These solvents may be used alone or in combination.Bases which can be used in this reaction are inorganic bases such assodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride,etc and organic bases such as, triethylamine, pyridine etc.

As to the amount of the base and the compound of the general formula(VI) or (VII) used in this reaction, it suffices to use 2 mole per moleof the compound of the general formula (I') when R^(4') representshydrogen atom in general formula (I') and an amount equimolar to thecompound of the general formula (I') when R^(4') represents C₁ -C₅ alkylgroup, but amounts in excess thereof will do.

The reaction time depends upon the reaction temperature and reactionscale, but it may properly be selected from a range of 30 minutes to 8hours.

Further, the salt of the compound of the general formula (I) wasobtained by reacting the compound of the general formula (I) with theacid.

The salt of the compound of the general formula (I) may be any ofpharmaceutically acceptable salt. For the acids usable in preparing thesalt, there are exemeplified, for example, inorganic acids such ashydrogen chloride, sulfuric acid, phosphoric acid etc, organiccarboxylic acids such as acetic acid, succinic acid, fumaric acid,tartaric acid and organic sufonic acids such as methanesulfonic acid,heptanesulfonic acid benzenesulfonic acid, toluenesulfonic acid. For thesolvents, there are exemplified, water, alcohol, chloroform,dichloromethane, ethyl acetate and the like.

The compound of the general formula (I) and its salt can be obtained bya conventional method.

Among the compounds of the present invention of which the typicalexamples are shown in Table 1 below, the preferred compounds are thosewhose R¹ and R², which may be the same or different, represent hydrogenatom, alkyl (e.g., C₁ -C₁₀ alkyl) group, lower alkenyl (e.g., C₂ -C₆alkenyl) group, lower alkoxyalkyl (e.g., C₂ -C₆ alkoxyalkyl) group oraralkyl (e.g., benzyl) group, R³ and R⁴, which may be the same ordifferent, represent hydrogen atom, lower alkyl (e.g., C₁ -C₆ alkyl)group, lower alkenyl (e.g., C₂ -C₆ alkenyl) group, lower alkoxyalkyl(e.g., C₂ -C₆ alkoxyalkyl) group, benzoyl group, lower acyl (e.g., C₂-C₆ alkylcarbonyl) group, lower alkoxycarbonyl (e.g., C₂ -C₆alkoxycarbonyl) group, lower alkylsulfonyl (e.g., C₁ -C₄ alkylsulfonyl)group or aralkyl group.

More preferred ones are those whose R¹ and R², which may be the same ordifferent, C₁ -C₆ alkyl group; C₁ -C₄ alkyl group substituted with C₁-C₅ alkoxy group, a phenyl group or a phenyl group substituted withhalogen atom, C₁ -C₄ alkyl group or C₁ -C₅ alkoxy group; or C₂ -C₅alkenyl group; R³ and R⁴ represents hydrogen atom or C₁ -C₄ alkyl group,R⁵, R⁶ and R⁷ represent hydrogen atom.

Representative examples of the compound of the general formula (I) andtheir salts will be shown in Table 1, but the derivatives are notlimited to these examples.

                                      TABLE 1                                     __________________________________________________________________________                                                          Physical property       Com-                                                  melting point           pound                                                 (°C.) or                                                               refrac-                 No. R.sup.1    R.sup.2     R.sup.3  R.sup.4  R.sup.5                                                                          R.sup.6                                                                          R.sup.7                                                                          tive                    __________________________________________________________________________                                                          index                   1   C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           H        H        H  H  H  m.p. 80-81°                                                            C.                      2   iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  H  H  m.p. 99-100°                                                           C.                      3   n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         H        H        H  H  H  m.p. 64-66°                                                            C.                      4   C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           CH.sub.3 CO                                                                            CH.sub.3 CO                                                                            H  H  H  paste                   5   iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CO                                                                            CH.sub.3 CO                                                                            H  H  H  m.p.                                                                          147-149° C.      6   n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 CO                                                                            CH.sub.3 CO                                                                            H  H  H  m.p. 97-99°                                                            C.                      7   n-C.sub.3 H.sub.7                                                                        n-C.sub. 3 H.sub.7                                                                         ##STR8##                                                                               ##STR9##                                                                              H  H  H  m.p.                                                                          145-147° C.      8   iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        C.sub.2 H.sub.5                                                                        H  H  H  paste                   9   iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CO                                                                            C.sub.2 H.sub.5                                                                        H  H  H  paste                   10  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 CO                                                                            C.sub.2 H.sub.5                                                                        H  H  H  paste                   11  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 CO                                                                            CH.sub.3 H  H  H  paste                   12  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 SO.sub.2                                                                      CH.sub.3 H  H  H  m.p. 99-101°                                                           C.                      13  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                          ##STR10##                                                                             CH.sub.3 H  H  H  paste                   14  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 SO.sub.2                                                                      C.sub.2 H.sub.5                                                                        H  H  H  m.p.                                                                          128-130° C.      15  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                          ##STR11##                                                                             CH.sub.3 H  H  H  m.p. 79-80°                                                            C.                      16  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p. 93.6°                                                             C.                      17  sec-C.sub.4 H.sub.9                                                                      sec-C.sub.4 H.sub.9                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p. 100.5°                                                            C.                      18  CH.sub.3   CH.sub.3    CH.sub.3 CH.sub.3 H  H  H  m.p. 176.8°                                                            C.                      19  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p. 145.1°                                                            C.                      20  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 CH.sub.3 H  H  H  m.p. 103.8°                                                            C.                      21  iso-C.sub.4 H.sub.9                                                                      iso-C.sub.4 H.sub.9                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p. 93-94°                                                            C.                      22  iso-C.sub.5 H.sub.11                                                                     iso-C.sub.5 H.sub.11                                                                      CH.sub.3 CH.sub.3 H  H  H  m.p. 91-93°                                                            C.                      23  n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                                                         CH.sub.3 CH.sub.3 H  H  H  m.p. 47-51°                                                            C.                      24  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p. 84-86°                                                            C.                      25  CH.sub.3   CH.sub.3    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p. 77-79°                                                            C.                      26  H.sub.2 CCHCH.sub.2                                                                      H.sub.2 CCHCH.sub.2                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p. 78-80°                                                            C.                      27  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.3 CH.sub.3 CH.sub.3                                                                         H  H  paste                   28  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CH.sub.3 CH.sub.3                                                                         H  H  paste                   29  n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                                                         CH.sub.3 CH.sub.3 CH.sub.3                                                                         H  H  paste                   30  n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5510                  31  n-C.sub.7 H.sub.15                                                                       n-C.sub.7 H.sub.15                                                                        CH.sub.3 CH.sub.3 H  H  H  m.p. 56-58°                                                            C.                      32  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 CH.sub.3                                                                         H  H  m.p.                                                                          103-106° C.      33  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        CH.sub.3                                                                         H  H  m.p. 75-77°                                                            C.                      34  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      H  H  H  m.p. 56-59°                                                            C.                      35  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       iso-C.sub.3 H.sub.7                                                                    iso-C.sub.3 H.sub.7                                                                    H  H  H  m.p. 82-84°                                                            C.                      36  CH.sub.2CHCH.sub.2                                                                       CH.sub.2CHCH.sub.2                                                                        C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p. 44-47°                                                            C.                      37  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5491                  38  iso-C.sub.4 H.sub.9                                                                      iso-C.sub.4 H.sub.9                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5469                  39  sec-C.sub.4 H.sub.9                                                                      sec-C.sub.4 H.sub.9                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5434                  40  t-C.sub.4 H.sub.9                                                                        t-C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p. 89-91°                                                            C.                      41  n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                                                         CH.sub.3 OCH.sub.2 CH.sub.2                                                            CH.sub.3 OCH.sub.2 CH.sub.2                                                            H  H  H  n.sub.D.sup.25                                                                1.5225                  42  t-C.sub.4 H.sub.9                                                                        t-C.sub.4 H.sub.9                                                                         CH.sub.3 OCH.sub.2 CH.sub.2                                                            CH.sub.3 OCH.sub.2 CH.sub.2                                                            H  H  H  n.sub.D.sup.25                                                                1.5337                  43  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         CH.sub.2CHCH.sub.2                                                                     CH.sub.2CHCH.sub.2                                                                     H  H  H  n.sub.D.sup.25                                                                1.5557                  44  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.2CHCH.sub.2                                                                     CH.sub.2CHCH.sub.2                                                                     H  H  H  n.sub.D.sup.25                                                                1.5559                  45  t-C.sub.4 H.sub.9                                                                        t-C.sub.4 H.sub.9                                                                         CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          118.5-121°                                                             C.                      46  n-C.sub.8 H.sub.17                                                                       n-C.sub.8 H.sub.17                                                                        CH.sub.3 CH.sub.3 H  H  H  m.p. 40-48°                                                            C.                      47  iso-C.sub.5 H.sub.11                                                                     iso-C.sub.5 H.sub.11                                                                      C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5106                  48  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                        ##STR12##                                                                              ##STR13##                                                                             H  H  H  n.sub.D.sup.23                                                                1.5744                  49  CH.sub.2CHCH.sub.2                                                                       CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2                                                                     CH.sub.2 CHCH.sub.2                                                                    H  H  H  paste                   50                                                                                 ##STR14##                                                                                ##STR15##  CH.sub.3 CH.sub.3 H  H  H  n.sub.D.sup.25                                                                1.5671                  51                                                                                 ##STR16##                                                                                ##STR17##  CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          39.5-40.1°                                                             C.                      52  n-C.sub.8 H.sub.17                                                                       n-C.sub.8 H.sub.17                                                                        C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p. 27-31°                                                            C.                      53  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                          ##STR18##                                                                              ##STR19##                                                                             H  H  H  n.sub.D.sup.25                                                                1.5732                  54  CH.sub.3   C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p. 98-100°                                                           C.                      55  CH.sub.3   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p.                                                                          79-80.5° C.      56  iso-C.sub.3 H.sub.7                                                                      C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p. 69-74°                                                            C.                      57  iso-C.sub.3 H.sub.7                                                                      C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  m.p.                                                                          63-63.5° C.      58  n-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p. 93-98°                                                            C.                      59  n-C.sub.4 H.sub.9                                                                        C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p. 44-47°                                                            C.                      60  iso-C.sub.4 H.sub.9                                                                      C.sub.2 H.sub.5                                                                           CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          50.5-56° C.      61  iso-C.sub.3 H.sub.7                                                                      n-C.sub.4 H.sub.9                                                                         CH.sub.3 CH.sub.3 H  H  H  n.sub.D.sup.25                                                                1.5595                  62  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.4 H.sub.9                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          74-76.5° C.      63                                                                                 ##STR20##                                                                                ##STR21##  CH.sub.3 CH.sub.3 H  H  H  m.p. 64-67°                                                            C.                      64  CH.sub.3   iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CH.sub. 3                                                                              H  H  H  m.p. 59-64°                                                            C.                      65  CH.sub.3   iso-C.sub.3 H.sub.7                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5554                  66  C.sub.2 H.sub.5                                                                          n-C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5565                  67  C.sub.2 H.sub.5                                                                          iso-C.sub.4 H.sub.9                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5523                  68  iso-C.sub.3 H.sub.7                                                                      n-C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5464                  69  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.4 H.sub.9                                                                       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5345                  70  C.sub.2 H.sub.5                                                                          CH.sub.3 O(CH.sub.2).sub.3                                                                CH.sub.3 CH.sub.3 H  H  H  n.sub.D.sup.25                                                                1.5620                  71  C.sub.2 H.sub.5                                                                          t-C.sub.4 H.sub.9                                                                         CH.sub.3 CH.sub.3 H  H  H  m.p. 33-40°                                                            C.                      72  C.sub.2 H.sub.5                                                                          t-C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                        H  H  H  n.sub.D.sup.25                                                                1.5511                  73  iso-C.sub.3 H.sub.7                                                                       ##STR22##  CH.sub.3 CH.sub.3 H  H  H  paste                   74  iso-C.sub.3 H.sub.7                                                                       ##STR23##  CH.sub.3 CH.sub.3 H  H  H  paste                   75  iso-C.sub.3 H.sub.7                                                                       ##STR24##  CH.sub.3 CH.sub.3 H  H  H  paste                   76  iso-C.sub.3 H.sub.7                                                                       ##STR25##  CH.sub.3 CH.sub.3 H  H  H  paste                   77  iso-C.sub.3 H.sub.7                                                                       ##STR26##  CH.sub.3 CH.sub.3 H  H  H  paste                   78  iso-C.sub.3 H.sub.7                                                                       ##STR27##  CH.sub.3 CH.sub.3 H  H  H  paste                   79  iso-C.sub.3 H.sub.7                                                                       ##STR28##  CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          119-120°                                                               C.                      80  iso-C.sub.3 H.sub.7                                                                       ##STR29##  CH.sub.3 CH.sub.3 H  H  H  paste                   81  iso-C.sub.3 H.sub.7                                                                       ##STR30##  CH.sub.3 CH.sub.3 H  H  H  paste                   82  iso-C.sub.3 H.sub.7                                                                       ##STR31##  CH.sub.3 CH.sub.3 H  H  H  paste                   83  C.sub.2 H.sub.5                                                                           ##STR32##  H.sub.3  CH.sub.3 H  H  H  paste                   84  C.sub.2 H.sub.5                                                                           ##STR33##  CH.sub.3 CH.sub.3 H  H  H  paste                   85                                                                                 ##STR34##                                                                                ##STR35##  CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          127-129° C.      86  C.sub.2 H.sub.5                                                                          iso-C.sub.3 H.sub.7                                                                       H        H        H  H  H  m.p. 83.5°                                                             C.                      87  sec-C.sub.4 H.sub.9                                                                      sec-C.sub.4 H.sub.9                                                                       H        H        H  H  H  m.p. 105.5-                                                                   107.5° C.        88  iso-C.sub.3 H.sub.7                                                                       ##STR36##  H        H        H  H  H  m.p. 94.0°                                                             C.                      89  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         H        H        H  CH.sub.3                                                                         H  m.p.                                                                          87.0-88.0°                                                             C.                      90  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  CH.sub.3                                                                         H  m.p. 102.0-                                                                   104.0° C.        91  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           H        H        H  CH.sub.3                                                                         H  m.p.                                                                          95.0-96.0°                                                             C.                      92  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           H        H        H  CH.sub.3                                                                         CH.sub.3                                                                         m.p.                                                                          88.0-90.0°                                                             C.                      93  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  CH.sub.3                                                                         CH.sub.3                                                                         m.p. 99.0-                                                                    101.0° C.        94  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       CH.sub.3 CH.sub.3 H  H  H  m.p.                                                                          149-150° C.                                                            (hydrochloric                                                                 acid salt)              95  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                           H        H        CH.sub.3                                                                         H  H  m.p. 145.0-                                                                   147.0° C.                                                              (hydrochloric                                                                 acid salt)              96  n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                         H        H        CH.sub.3                                                                         H  H  m.p. 120.0-                                                                   124.0° C.                                                              (decomposed)                                                                  (hydrochloric                                                                 acid salt)              97  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        CH.sub.3                                                                         H  H  m.p. 143.0-                                                                   147.0° C.                                                              (hydrochloric                                                                 acid salt)              98  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  CH.sub.3                                                                         H  m.p. 145.0-                                                                   148.0° C.                                                              (fumaric acid                                                                 salt)                   99  iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  CH.sub.3                                                                         H  m.p. 150.0-                                                                   152.0° C.                                                              (sulfuric acid                                                                salt)                   100 iso-C.sub.3 H.sub.7                                                                      iso-C.sub.3 H.sub.7                                                                       H        H        H  CH.sub.3                                                                         H  m.p. 135.0-                                                                   137.0° C.                                                              (hydrochloric                                                                 acid                    __________________________________________________________________________                                                          salt)               

Next, in table 2 are shown NMR spectra data of the compounds whosephysical properties are expressed in term "paste" in Table 1.

                  TABLE 2                                                         ______________________________________                                        Compound                                                                      No.      NMR data (60 MHz, CDCl.sub.3, δvalue)                          ______________________________________                                         8       1.13 (3H, t, J=7.0 Hz), 1.30 (12H, d, J=7.0 Hz),                              2.30-3.30 (7H, m), 4.40 (1H, d, J=3.6 Hz), 4.65                               (1H, d, J=3.6 Hz), 5.35 (2H, m)                                       9       1.03 (3H, t, J=6.6 Hz), 1.32 (12H, d, J=7.0 Hz),                              1.15 (3H, s), 2.10-4.20 (6H), 4.30 (1H, d,                                    J=4.0 Hz), 5.08 (2H, m), 6.35 (1H, d, J=4.0 Hz)                      10       0.95 (3H, t, J=6.4 Hz), 1.03 (3H, t, J=6.4 Hz),                               1.30-1.95 (4H, m), 2.15 (3H, s), 2.0-4.30 (6H,                                m), 4.15 (4H, t, J=6.0 Hz), 4.30 (1H, d,                                      J=3.6 Hz), 6.35 (1H, d, J=3.6 Hz)                                    11       1.0 (6H, t, J=7.0 Hz), 1.65 (4H, m), 2.30 (3H,                                s), 2.40 (3H, s), 2.0-4.10 (4H), 3.90 (1H, d,                                 J=4.0 Hz), 4.15 (4H, t), 6.40 (1H, d, J=4.0 Hz)                      13       0.97 (6H, t, J=7.0 Hz), 1.75 (4H, m), 2.40 (3H,                               s), 2.20-4.20 (4H, m), 3.90 (1H, d, J-32 4.0 Hz),                             4.33 (4H, t, J=6.4 Hz), 6.32 (1H, d, J=4.0 Hz),                               7.40 (5H, s)                                                         27       0.97 (6H, t, J=6.8 Hz), 1.33-2.0 (4H, m), 1.80                                (3H, s), 2.47 (6H, s), 2.47-3.20 (4H, m), 4.13                                (4H, t, J=6.4 Hz), 4.33 (1H, s)                                      28       1.30 (12H, d, J=7.0 Hz), 1.70 (3H, s , 2.47 (6H,                              s), 2.47-3.10 (4H, m), 4.37 (1H, s), 5.10 (2H,                                m)                                                                   49       2.30-3.80 (8H, m), 4.72 (2H, s), 4.50-4.83 (4H,                               m), 4.97-6.30 (12H, m)                                               73       1.20 (6H, d, J=7.0 Hz), 2.45(6H, s), 2.20-3.25                                (4H, m), 4.55 (2H, s), 5.05 (1H, m), 5.20 (2H,                                s), 7.30 (5H, m)                                                     74       1.20 (6H, d, J=7.0 Hz), 2.30 (3H, s), 2.45 (2H,                               s), 2.25-3.20 (4H, m), 4.55 (2H, s), 5.05 (1H,                                m), 5.15 (2H, s), 7.05 (2H, d, J=8.0 Hz), 7.25                                (2H, d, J=8.0 Hz)                                                    75       1.18 (6H, d, J=7.0 Hz), 2.45 (6H, s), 2.30-3.20                               (4H, m), 3.75 (3H, s), 4.56 (2H, s), 5.03 (1H,                                m), 5.13 (2H, s), 6.80 (2H, d, J=8.0 Hz), 7.26                                (2H, d, J=8.0 Hz)                                                    76       1.20 (6H, d, J=6.8 Hz), 2.40 (6H, s), 2.30-3.30                               (4H, m), 4.56 (2H, s), 5.03 (1H, m), 5.33 (2H,                                s), 7.25 (4H, s)                                                     78       1.26 (6H, d, J=6.2 Hz), 1.55 (3H, d, J=6.6 Hz),                               2.42 (6H, s), 2.20-3.20 (4H, m), 4.53 (1H, d,                                 J=3.0 Hz), 4.63 (1H, d, J=3.0 Hz), 5.10 (1H, m),                              5.92 (1H, q, J=6.6 Hz), 7.30 (4H, s)                                 80       1.30 (6H, d, J=6.0 Hz), 1.55 (3H, d, J=7.0 Hz),                               2.40 (6H, s), 2.30-3.25 (4H, m), 4.45 (1H, d,                                 J=3.0 Hz), 4.70 (1H, d, J=3.0 Hz), 5.15 (1H, m),                              5.88 (1H, q, J=7.0 Hz), 7.05-7.50 (3H, m)                            81       1.25 (6H, d, J=6.6 Hz), 1.55 (3H, d, J=6.4 Hz),                               2.30 (3H, s), 2.43 (6H, s), 2.20-3.15 (4H), 4.50                              (1H, m), 5.93 (1H, q, J=6.4 Hz), 6.99-7.40 (4H,                               (1H, d, J=3.0 Hz), 4.60 (1H, d, J=3.0 Hz), 5.10                               m)                                                                   82       1.25 (6H, d, J=6.8 Hz), 1.55 (3H, d, J=6.0 Hz),                               2.40 (6H, s), 2.15-3.20 (4H, m), 3.73 (3H, s),                                4.47 (1H, d, J=3.2 Hz), 4.57 (1H, d, J=3.2 Hz),                               5.07 (1H, m), 5.90 (1H, q, J=6.0 Hz), 6.60-6.95                               (2H, m), 7.10-7.40 (2H, m)                                           83       1.25 (3H, t, J=6.8 Hz), 1.56 (3H, d, J=6.0 Hz),                               2.40 (6H, s), 2.20-3.20 (4H, m), 4.20 (2H, q,                                 J=6.8 Hz), 4.45 (1H, d, J=3.0 Hz), 4.60 (1H, d,                               J=3.0 Hz), 5.90 (1H, q, J=6.0 Hz), 7.20 (4H, s)                      84       1.26 (3H, t, J=7.0 Hz), 1.63 (3H, d, J=6.4 Hz),                               2.4 (6H, s), 2.20-3.20 (4H, m), 4.25 (2H, q,                                  J=7.0 Hz), 4.50 (1H, d, J=2.2 Hz), 4.65 (1H, d,                               J=2.2 Hz), 6.0 (1H, d, J=6.4 Hz), 7.30 (5H, m)                       ______________________________________                                    

Malonic acid derivative represented by the general formula (I) and theirsalts caused no toxic symptom nor death in mice or rats even afteradministered continually for two weeks at a dose of 300 mg/kg/day to themice or rats, which reveals the markedly low toxicity of the compound ofthis invention. For example, LD₅₀ value (acute oral toxicity to malerat) of the compound No. 20 is more than 1,000 mg/kg.

The compound represented by the general formula (I) and their salts isuseful as a medicinal agent for treating liver diseases. For example,while it is known that hepatic disorders can be experimentally producedin healthy test animals by administering various agents such as carbontetrachloride to the animals, as disclosed for example in U.S. Pat. No.4,118,506, it has been found that the compound represented by thegeneral formula (I) and their salts gives a marked effect of suppressingthe lowering of liver functions or improving said functions whenadministered orally or parenterally (for example by injection) to testanimals which have hepatic disorders of various pathologic modelsexperimentally produced therein. Accordingly, the compound representedby the general formula (I) and their salts is useful as a medicinalagent for curing or preventing hepatic disorders in men and animals.Thus, it can be used as a curative for acute or chronic hepaticdisorders of men and animals produced by various causes, for example,jecur adiposum, alcholic hepatitis, hepatitis, toxic liver disorders,cardiac cirrhosis, cholestatic liver disorder, or hepatocirrhosis whichis the final state of these diseases.

Accordingly, the term "a pharmaceutical composition for treating hepaticdisorders" as used in this invention means a medicinal agent for curingand/or preventing various disorders in liver by utilizing thepharmacological actions manifested in liver as mentioned above includingthe action of activating liver functions and the action of preventingand curing hepatic disorders.

The compound represented by the general formula (I) and their salts canbe used as a medicinal agent for treating hepatic disorders in the formas it is; it may also be formulated, according to conventionalpharmaceutical procedures, as a mixture thereof with a pharmaceuticallyacceptable diluents and/or other pharmacologically active substances.Further, it may be formulated into a dose unit form. Examples of theform which the compound can take as a medicinal agent include: powders,granules, tablets, dragee, capsules, pills, suspensions, solutions,liquid, emulsions, ampules, injections, and isotonic solutions.

The modes of preparing the compound of this invention into apharmaceutical composition include one wherein the compound representedby the general formula (I) and their salts is contained as a mixturethereof with one or more pharmaceutically acceptable diluents.

The "diluent" referred to herein means a material other than thecompound represented by the general formula (I) and their salts. It maybe in the form of solid, semisolid, liquid, or ingestible capsules.Examples of the diluents include excipients, filles, binders, moisteningagents, disintegrators, surfactants, lubricants, dispersants, bufferingagents, flavoring agents, odor correctives, coloring agents, flavors,preservatives, solubilizing aids, solvents, coating agents, andsugar-coating agents. However, they are not limited to these. Further,they may be used as a mixture of one or more kinds thereof. Sometimes,these pharmaceutically acceptable diluents are used as a mixture thereofwith other pharmacologically active substances.

The pharmaceutical composition according to this invention may beprepared by any method known in the art. For instance, the activeingredient is mixed with a diluent and made up, for example, intogranules. The resulting composition is then formed, for example, intotablets. Preparations to be administered parenterally should be madeaseptic. Further, as occasion demands, they should be made isotonic withblood.

In this invention, since the compound represented by the general formula(I) and their salts mentioned above can be itself make a medicinal agentfor treating liver diseases, the active ingredient is generallycontained in the composition in a proportion of 0.01 to 100% by weight.

When the compound is made into a preparation in the form of dose unit,the individual parts of the preparation which form said preparation maybe either in the same shape or in shapes different from each other. Forexample, the following shapes are often adopted: tablets, granules,pills, powders, dragee, capsules, ampules, and the like.

The medicinal agent for treating hepatic disorders according to thisinvention can be applied to men and animals for the purpose ofpreventing and treating hepatic disorders therein, in a mannerconventional in the art. It is administered orally or parenterally. Oraladministration referred to herein includes sublingual administration.Parenteral administration includes herein administrations conducted bymeans of injections (including, for example, subcutaneous, intramuscularor intravenous injection and instillation).

The dose of the medicinal agent of this invention varies depending uponvarious factors including whether it is applied to animals or men,difference in susceptibility, age, sex, body weight, the method, time,and interval of administration, the condition of diseases, physicalcondition, the properties of the pharmaceutical composition, the kind ofthe preparation, and the kind of the active ingredient.

Accordingly, sometimes those doses may be sufficient which are lowerthan the minimum of the dose range shown below, whereas sometimes itbecomes necessary to administer an amount exceeding the upper limit ofthe dose shown below.

When the pharmaceutical composition is to be administered in a largeamount, it is preferably administered divided in several doses per day.

In order to obtain effective results in application to animals, theagent is advantageously administered at a dose, in terms of the activeingredient, in the range of 0.1 to 500 mg, preferably 0.1 to 30 mg, per1 kg of body weight per day in oral administration, and 0.01 to 250 mg,preferably 0.1 to 25 mg, per 1 kg of body weight per day in the case ofparenteral administration.

The doses necessary for obtaining effective results in application tomen are, judged from the effective doses in animals and in considerationof difference in susceptibility and safety, advantageously selected, forexample from the following dose range. In oral administration the doseis 0.1 to 200 mg, preferably 0.5 to 50 mg, per kg of body weight perday, and in parenteral administration it is 0.01 to 100 mg, preferably0.1 to 25 mg, per kg of body weight per day.

EXAMPLE

This invention will be described in detail below with reference toExamples, but it is in no way limited thereto.

First, synthesis examples of this invention are shown below.

Example 1

Diisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate(compound No. 2)

To a suspension of 2.5 g of glyoxal-sodium bisulfite in 10 ml of waterwas added dropwise 0.5 g of ethylenediamine with ice-cooling and themixture was stired for additional 1 hour. To this solution was addeddropwise with ice-cooling the dithiolate aqueous solution which had beenprepared previously by the reaction of 1.5 g of diisopropyl malonatewith 0.8 g of carbon disulfide in the presence of 3.3 g of 30% aqueouspotassium hydroxide.

After the reaction mixture was stirred at 10° C. for additional 1 hour,the solid precipitated was collected by filtration, washed with waterand n-hexane, and then recrystallized from chloroform-n-hexane to give1.6 g of the desired product.

Yield 58%; m.p. 99°-100° C.

Example 2

Diisopropyl(2,5-diacetyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 5)

In the mixed solution of 10 ml of pyridine and 10 ml of tetrahydrofuranwas dissolved 1.0 g ofdiisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate,and 0.8 g of acetyl chloride was added dropwise at 10° C. and themixture was stirred for 1 hour.

After the solvents were evaporated in vacuo, the residue was extractedwith ethyl acetate and dried over sodium sulfate. The extract wasconcentrated and purified by silica gel chromatography. The solidobtained was recrystalized from ethyl acetate-n-hexane to give 1.0 g ofthe desired product as a white crystal.

Yield 80%; m.p. 147°-149° C.

Example 3

Diisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-yliene)malonate.(Compound No. 16)

To the solution of 1.9 g of N,N'-dimethylethylene diamine in 10 ml ofwater was added 3.2 g of 40% aqueous solution of glyoxal dropwise at 0°C. and the mixture was stirred at 0° C. for 30 minutes. To this solutionwas added dropwise at 0° C. the dithiolate solution, which had beenprepared previously by the reaction of 3.7 g of diisopropyl malonatewith 1.8 g of carbon disulfide in the presence of 30% aqueous potassiumhydroxide solution, and the mixture was stirred for additional 16 hours.

Then, 50 ml of water was added to the reaction solution. The solidprecipitated was collected by filtration and recrystalized from ethylacetate-n-hexane to give 5.1 g of the desired product.

Yield 69%; m.p. 93.6° C.

Example 4

Diisopropyl(2,5-diethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 24)

To a suspension of 4.3 g of glyoxal sodium bisulfite in 10 ml of waterwas added 1.9 g of N,N'-diethylethylenediamine dropwise with ice-coolingand the mixture was stirred at 25° C. until it became a homogeneoussolution. The mixture was cooled to -10° C. and the dithiolate solutionwhich had been prepared previously by the reaction of 2.8 g ofdiisoopropyl malonate with 1.4 g of carbon disulfide in 10 ml ofdimethylsulfoxide in the presence of 7.3 g of 30% aqueous potassiumhydroxide, was added dropwise. After the reaction mixture was stirredfor additional 1 hour, 50 ml of water was added to the reactionsolution. The solid deposited was collected by filtration andrecrystalized from ethyl acetate-n-hexane to give 4.1 g of the desiredproduct.

Yield 68%; m.p. 84°-86° C.

Example 5

Diethyl(1,2,5-trimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 32)

In 40 ml of water was suspended 11.2 g of pyruvic aldehyde sodiumbisulfite addition compound, and 2.3 g of N,N'-dimethylethylenediaminewas added dropwise at 0° C. and the mixture was stirred for additional 1hour. To this solution was added dropwise at 0° C. the dithiolatesolution, which had been prepared previously by the reaction of 3.2 g ofdiethyl malonate with 1.8 g of carbon disulfide in 20 ml ofdimethylsulfoxide in the presence of 9.7 g of 30% aqueous potassiumhydroxide. After the reaction mixture was stirred for additional 1 hour,50 ml of water was added to the solution. The solid precipitated wascollected by filtration and recrystallized from ethyl acetate-n-hexaneto give 1.7 g of the desired product.

Yield 24%; 103°-106° C.

Example 6

Diisopropyl(2,5-diisopropyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 35)

To a suspension of 1.7 g of glyoxal sodium bisulfite in 12 ml of waterwas added N,N'-diisopropylethylenediamine dropwise at room temperatureand the mixture was stirred until it became a homogeneous solution. Tothis solution was added dropwise at 0° C. the dithiolate solution whichhad been prepared previously by the reaction of 1.13 g of diisopropylmalonate with 0.55 g of carbon disulfide in the presence of 2.9 g of 30%aqueous potassium hydroxide. After the mixture was stirred foradditional 30 minutes, 50 ml of water was added to the reactionsolution. The solid deposited was collected by filtration andrecrystalized from ethyl acetate-n-hexane to give 1.16 g of the desiredproduct.

Yield 45%; m.p. 82°-84° C.

Example 7

Diisopropyl(2,5-diallyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 44)

To a suspension of 1.85 g glyoxal sodium bisulfite in 13 ml of water wasadded dropwise 1.0 g of N,N'-diallylethylenediamine with ice-cooling andthe mixture was stirred until it became a homogeneous solution. To thissolution was added dropwise with ice-cooling the dithiolate solutionwhich had been prepared previously by the reaction of ;b 1.22 g ofdiisopropyl malonate with 0.59 g of carbon disulfide in the presence of3.15 g of 30% aqueous potassium hydroxide. After the mixture was stirredfor additional 1 hour, the oily product deposited was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate,concentrated and purified by column chromatography on silica gel to give1.8 g of the desired product as a viscous oil.

Yield 65%; n_(D) ²⁵ : 1.5559.

Example 8

Isopropyl4-methoxybenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicycl-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 75)

To a suspension of 2.5 g of glyoxal sodium bisulfite in 20 ml of waterN,N'-dimethylethylenediamine was added dropwise at 0° C. and was stirredfor 1 hour. To this solution was added at 0° C. the dithiolate solutionwhich had been prepared previously by the following method; To asolution of 2.0 g of isopropyl 4-methoxybenzyl malonate and 0.8 g ofcarbon disulfide was added 3.3 g of 30% aqueous potassium hydroxide withice-cooling and the mixture was stirred for 15 minutes at the sametemperature and for 40 minutes at room temperature.

The reaction mixture was stirred for additional 1 hour, and extractedwith ethyl acetate. The extract was dried over anhydrous sulfate,concentrated and purified by column chromatography on silica gel to give1.8 g of the desired product as paste.

Yield 52%.

NMR data (60 MHz, CDCl₃, δ value) 1.18 (6H, d, J=7.0 Hz), 2.45 (6H, s),2.28-3.20 (4H, m), 3.75 (3H, s), 4.56 (2H, s), 5.03 (1H, m), 5.13 (2H,s), 6.80 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0 Hz)

Example 9

Diisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 16)

In 10 ml of water was dissolved 3.2 g of 40% aqueous glyoxal and 1.9 gof N,N'-dimethylethylenediamine at 0° C. To this solution was added 4.4g of sodium bisulfite dissolved in 20 ml of water and the mixture wasstirred for 30 minutes. To this was added dropwise at 0° C. thedithiolate solution which had been prepared previously by the reactionof 3.7 g of diisopropyl malonate with 1.8 g of carbon disulfide in thepresence of 8 g of 30% aqueous potassium hydroxide. After the reactionmixture was stirred for additional 3 hours, 50 ml of water was added tothe reaction solution. The solid deposited was collected by filtrationand recrystalized from ethyl acetate-n-hexane to give 5.5 g of thedesired product.

Yield 74%; m.p. 93.6° C.

Example 10

Diisopropyl(3-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.(Compound No. 90)

To a suspension of 17.4 g of glyoxal sodium bisulfite in 120 ml of waterwas added dropwise 7.1 g of propylenediamine at 0° C. and the mixturewas stirred for 1 hour. Then to this solution was added dropwise at 0°C. the dithiolate solution, which had been prepared previously asfollow; To a mixture of 15.04 g of diisopropyl malonate and 6.4 g ofcarbon disulfide was added dropwise with ice-cooling 23.8 g of 45%aqueous potassium hydroxide solution and was stirred at the sametemperature for 1 hour.

After stirring for 15 minutes, the reaction mixture was extracted withdichloromethane and washed with water. The extract was dried overmagnesium sulfate and concentrated to afford syrup, which wasrecrystallized from ether-n-hexane to give 11.5 g of the desired productas a white crystal.

Yield 40%; m.p. 102°-104° C.

Example 11

Diisopropyl(3-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonatesulfuric acid salt. (Compound No. 99)

In 30 ml of dichloromethane was dissolved 1.8 g ofdiisopropyl(3-methyl-2,5-diaza-7,9dithiabicyclo-[4,3,0]-nonane-8-yidene)malonate,and a solution consist of 0.51 g of concentrated sulfuric acid and 0.5ml of ethanol was added dropwise with ice-cooling and stirred for 15minutes. The solution was evaporated in vacuo and the precipitatedcrystal was collected and washed with ether-n-hexane to give 2.0 g ofthe desired product as a white crystal.

Yield 87.0%; m.p. 150.0°-152.0° C.

Example 12

Di-n-propyl(6-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonatehydrochloride salt (compound No. 96)

To a solution of 16.64 g of sodium bisulfite in 160 ml of water wasadded 14.4 g of 40% aqueous pyruvic aldehyde and the mixture was stirredat room temperature for 30 minutes. After the solution was cooled downto 0° C., 5.8 g of ethylenediamine was added dropwise, and the mixturewas stirred for 10 minutes. To this was added dropwise at 0° C. thedithiolate solution, which had been prepared previously by the reactionof 15.04 g of di-n-propyl malonate with 6.4 g of carbon disulfide in thepresence of 23.8 g of 45% aqueous potassium hydroxide, and the mixturewas stirred for 30 minutes at the same temperature. The reaction mixturewas extracted three times with each 200 ml of chloroform.

The combined extract was washed with water and dried over magnesiumsulfate. Into this solution was bubbled dry hydrogen chloride withice-cooling. After the solution was saturated with hydrogen chloride,the solvent was removed. The crystal precipitated was collected andwashed with ether-n-hexane to give 12.4 g of the desired product.

Yield 38.1%; m.p. 120.0-124.0 (dec.)

Now, Examples regarding pharmaceutical compositions according to thisinvention will be described below. In the Examples, "part" is all partby weight. It is needless to say that the kinds and the proportions ofthe compounding ingredients used in the composition according to thisinvention can be changed variously without being restricted by theseExamples.

Example 13

    ______________________________________                                        Compound No. 2    10 parts                                                    Heavy magnesium oxide                                                                           10 parts                                                    Lactose           80 parts                                                    ______________________________________                                    

The above ingredients were mixed uniformly and made into a medicinalpreparation in the form of powders or fine granules.

Example 14

    ______________________________________                                        Compound No. 16     10 parts                                                  Synthetic aluminum silicate                                                                       10 parts                                                  Calcium hydrogen phosphate                                                                         5 parts                                                  Lactose             75 parts                                                  ______________________________________                                    

The above ingredients were used to be made up into powders in a similarmanner to that in Example.

Example 15

    ______________________________________                                        Compound No. 23   50 parts                                                    Starch            10 parts                                                    Lactose           15 parts                                                    Crystalline cellulose                                                                           20 parts                                                    polyvinyl alcohol  5 parts                                                    Water             30 parts                                                    ______________________________________                                    

The above ingredients were uniformly mixed, kneaded, then crushed,granulated, dried and sieved to obtain granules.

Example 16

A mixture of 99 parts of the granules obtained in Example 15 and 1 partof calcium stearate was compression-formed into tablets of 10 mmdiameter.

Example 17

    ______________________________________                                        Compound No. 49 78 parts                                                      Polyvinyl alcohol                                                                              2 parts                                                      Lactose         20 parts                                                      Water           30 parts                                                      ______________________________________                                    

The above ingredients were made up into granules in the same manner asin Example 15. Ten parts of crystalline cellulose was added to 90 partsof the granules obtained above, and the mixture was compression-moldedto obtain tablets of 8 mm diameter. The tablets may be further made upinto dragee by using, in appropriate amounts, a mixed suspension ofsyrup gelatin and precipitated calcium carbonate, and a coloring agent.

Example 18

    ______________________________________                                        Compound No. 56  0.5 part                                                     Nonionic surfactant                                                                            2.5 parts                                                    Physiological saline                                                                            97 parts                                                    ______________________________________                                    

The above ingredients were mixed with warming, and then sterilized toobtain injections.

Example 19

The powders obtained in Example 13 were filled into capsule containersavailable on the market to obtain capsules.

The effect of the compound of the present will be illustrated by thefollowing Test Examples.

Test Example 1

Effect of suppressing hepatic disorder caused by carbon tetrachloride.

Test Method

The test compound was dissolved or suspended in olive oil, and orallyadministered at a dose of 30 mg/kg to mice (6 weeks of age, dd-strain,♂). Six hours thereafter, carbon tetrachloride was orally administeredin a proportion of 0.05 ml/kg. The animals were sacrificed 24 hoursafter the administration of carbon tetrachloride, and the extent ofliver injury was grossly examined.

On the other hand, blood was collected from the animal at the time ofthe sacrifice, and centrifuged to obtain plasma. The plasma glutamicpyruvic transminase (GPT) activity was determined according to themethod of Reitman-Frankel. The activity was expressed in terms of KarmenUnits (K.U.). The conditions of the liver were expressed in terms ofliver injury index as follows.

    ______________________________________                                        Liver injury index                                                                             Condition of liver                                           ______________________________________                                        0                Healthy liver                                                2                Slightly affected                                            4                Evidently observed injury                                    6                Serious injury                                               ______________________________________                                    

Mice were used in groups of five and the results of test wererepresented by the mean value. When the GPT activity was 2,100 units orhigher, or further determination was made, and the activity wascalculated as 2,100 units for reasons of convenience.

The results obtained are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Effect of carbon tetrachloride on liver injury                                No. of compound Liver                                                         of this invention                                                                             injury index                                                                             p-GPT (K.U.)                                       ______________________________________                                        Administration of carbon                                                                      5.4        >2,100                                             tetrachloride alone                                                           No treatment    0                                                              1              2.0        225                                                 2              0.3        24.4                                                3              0.1        53.0                                               10              4.5        2,000                                              16              0.6        32                                                 18              1.8        166                                                19              1.6        99                                                 23              1.2        10.2                                               25              0.4        13.2                                               28              1.5        547                                                30              0.8        22.8                                               33              1.2        925                                                37              1.4        143                                                40              1.8        164                                                43              0.2        51                                                 49              1.2        23.8                                               51              0.4        18.2                                               54              0          13.4                                               56              0          16.8                                               59              0.5        109.2                                              63              0.5        32.8                                               67              2.5        1,620                                              68              1.5        914.6                                              72              0.4        428.6                                              74              0.6        25                                                 75              0          20                                                 79              1.4        1,060                                              81              1.2        120                                                83              0.8        38.6                                               84              0.8        37                                                 87              0.2        21                                                 94              2.0        1,534                                              96              0.1        28.0                                               97              0.2        45.0                                               ______________________________________                                    

What is claimed is:
 1. A malonic acid derivative represented by theformula (I); ##STR37## wherein R¹ and R², which may be the same ordifferent, represent hydrogen atom; C₁ -C₁₂ alkyl group; C₁ -C₈ alkylgroup substituted with C₁ -C₅ alkoxy group, a tetrahydrofuryl group, aphenyl group or a phenyl group substituted with 1 to 3 groups selectedfrom the group consisting of halogen atoms, C₁ -C₅ alkyl groups and C₁-C₅ alkoxy groups; or C₂ -C₆ alkenyl group; R³ and R⁴, which may be thesame or different, represent hydrogen atom, C₁ -C₆ alkyl group, C₂ -C₆alkenyl group, C₂ -C₈ alkoxyalkyl group, benzoyl group, C₂ -C₈alkylcarbonyl group, C₂ -C₈ alkoxycarbonyl group, C₁ -C₄ alkyl sulfonylgroup or benzyl group, and R⁵, R⁶ and R⁷, which may be the same ordifferent, represent hydrogen atom or C₁ -C₄ alkyl group or itspharmaceutically acceptable salts.
 2. A malonic acid derivative or itspharmaceutically acceptable salts according to claim 1, wherein R¹ andR², which may be the same or different, represent hydrogen atoms, alkylgroups, lower alkenyl groups, lower alkoxyalkyl groups or phenylalkylgroups which may be substituted with halogen atoms, lower alkyl groupsor lower alkoxy groups, R³ and R⁴, which may be the same or different,represent hydrogen atoms, lower alkyl groups, lower alkenyl groups,lower alkoxyalkyl groups, benzoyl groups, lower alkyl carbonyl groups,lower alkoxycarbonyl groups, lower alkylsulfonyl groups or benzylgroups.
 3. A malonic acid derivative or its pharmaceutically acceptablesalts as in either claim 1 or 2, wherein R¹ and R², which may be thesame or different, represent C₁ -C₆ ;l alkyl group; C₁ -C₄ alkyl groupsubstituted with C₁ -C₅ alkoxy group, a phenyl group or a phenyl groupsubstituted with halogen atom, C₁ -C₄ alkyl group or C₁ -C₅ alkoxygroup; or C₂ -C₅ alkenyl group; R³ and R⁴ represent hydrogen atom or C₁-C₄ alkyl group, R⁵, R⁶ and R⁷ represent hydrogen atom.
 4. A malonicacid derivative as in any one of claims 1 or 2 which isdiisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.5. A malonic acid derivative as in any one of claims 1 or 2 which isdi-n-propyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.6. A malonic acid derivative as in any one of claims 1 or 2 which isdiisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.7. A malonic acid derivative as in any one of claims 1 or 2 which isdi-n-propyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.8. A malonate acid derivative as in any one of claims 1 or 2 which isethylisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.9. A malonic acid derivative as in any one of claims 1 or 2 which isethyln-propyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.10. A malonic acid derivative as in any one of claims 1 or 2 which isisopropylp-methylbenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.11. A malonic acid derivative as in any one of claims 1 or 2 which isn-propylp-chlorobenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.12. A pharmaceutical composition for treating liver damage, comprisingan effective amount of a malonic acid derivative represented by theformula (I) ##STR38## wherein R¹ and R², which may be the same ordifferent, represent hydrogen atom; C₁ -C₁₂ alkyl group; C₁ -C₈ alkylgroup substituted with C₁ -C₅ alkoxy group, a tetrahydrofuryl group, aphenyl group or a phenyl group substituted with 1 to 3 groups selectedfrom the group consisting of halogen atoms, C₁ -C₅ alkyl groups and C₁-C₅ alkoxy groups, or C₂ -C₆ alkenyl group; R³ and R⁴, which may be thesame or different, represent hydrogen atom, C₁ -C₆ alkyl group, C₂ -C₆alkenyl group, C₂ -C₈ alkoxyalkyl group, benzoyl group, C₂ -C₈alkylcarbonyl group, C₂ -C₈ alkoxycarbonyl group, C₁ -C₄ alkylsulfonylgroup or benzyl group, and R⁵, R⁶ and R⁷, which may be the same ordifferent, represent hydrogen atom or C₁ -C₄ alkyl group or itspharmaceutically acceptable salts, and a pharmaceutically acceptablecarrier.
 13. A pharmaceutical composition according to claim 12, whereinR¹ and R², which may be the same or different, represent hydrogen atoms,alkyl groups, lower alkenyl groups, lower alkoxyalkyl groups orphenylalkyl groups which may be substituted with halogen atoms, loweralkyl groups or lower alkoxy groups, R³ and R⁴, which may be the same ordifferent, represent hydrogen atoms, lower alkyl groups, benzoyl groups,lower alkyl carbonyl groups, lower alkoxycarbonyl groups, loweralkylsulfonyl groups or aralkyl groups.
 14. A pharmaceutical compositionaccording to claim 12 or 13, wherein R¹ and R², which may be the same ordifferent, C₁ -C₆ alkyl group; C₁ -C₄ alkyl group substituted with C₁-C₅ alkoxy group, a phenyl group or a phenyl group substituted withhalogen atom, C₁ -C₄ alkyl group or C₁ -C₅ alkoxy group; or C₂ -C₅alkenyl group; R³ and R⁴ represents hydrogen atom or C₁ -C₄ alkyl group,R⁵, R⁶ and R⁷ represent hydrogen atom.
 15. A pharmaceutical compositionas in any one of claims 12 or 13 in which said malonic acid derivativeisdiisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.16. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative isdi-n-propyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.17. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative isdiisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.18. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative isdi-n-propyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.19. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative is ethylisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.20. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative is ethyln-propyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.21. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative is isopropylp-methylbenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.22. A pharmaceutical composition as in any one of claims 12 or 13 inwhich said malonic acid derivative is n-propylp-chlorobenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate.